eprintid: 10127656
rev_number: 14
eprint_status: archive
userid: 608
dir: disk0/10/12/76/56
datestamp: 2021-05-12 08:36:06
lastmod: 2021-09-23 22:36:48
status_changed: 2021-05-12 08:36:06
type: article
metadata_visibility: show
creators_name: Moore, G
creators_name: Lightner, C
creators_name: Elbai, S
creators_name: Brady, L
creators_name: Nicholson, S
creators_name: Ryan, R
creators_name: O'Sullivan, KE
creators_name: O'Byrne, KJ
creators_name: Blanco-Aparicio, C
creators_name: Cuffe, S
creators_name: O'Neill, M
creators_name: Heavey, S
creators_name: Finn, SP
creators_name: Gately, K
title: Co-Targeting PIM Kinase and PI3K/mTOR in NSCLC
ispublished: pub
divisions: UCL
divisions: B02
divisions: C10
divisions: D16
divisions: G88
keywords: NSCLC, PI3K-mTOR, PIM kinase, biomarker, c-Myc, drug resistance, miRNA, tumor tissue explants
note: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
abstract: PIM kinases are constitutively active proto-oncogenic serine/threonine kinases that play a role in cell cycle progression, metabolism, inflammation and drug resistance. PIM kinases interact with and stabilize p53, c-Myc and parallel signaling pathway PI3K/Akt. This study evaluated PIM kinase expression in NSCLC and in response to PI3K/mTOR inhibition. It investigated a novel preclinical PI3K/mTOR/PIM inhibitor (IBL-301) in vitro and in patient-derived NSCLC tumor tissues. Western blot analysis confirmed PIM1, PIM2 and PIM3 are expressed in NSCLC cell lines and PIM1 is a marker of poor prognosis in patients with NSCLC. IBL-301 decreased PIM1, c-Myc, pBAD and p4EBP1 (Thr37/46) and peIF4B (S406) protein levels in-vitro and MAP kinase, PI3K-Akt and JAK/STAT pathways in tumor tissue explants. IBL-301 significantly decreased secreted pro-inflammatory cytokine MCP-1. Altered mRNA expression, including activated PIM kinase and c-Myc, was identified in Apitolisib resistant cells (H1975GR) by an IL-6/STAT3 pathway array and validated by Western blot. H1975GR cells were more sensitive to IBL-301 than parent cells. A miRNA array identified a dysregulated miRNA signature of PI3K/mTOR drug resistance consisting of regulators of PIM kinase and c-Myc (miR17-5p, miR19b-3p, miR20a-5p, miR15b-5p, miR203a, miR-206). Our data provides a rationale for co-targeting PIM kinase and PI3K-mTOR to improve therapeutic response in NSCLC.
date: 2021-04-29
date_type: published
official_url: http://dx.doi.org/10.3390/cancers13092139
oa_status: green
full_text_type: pub
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 1863597
doi: 10.3390/cancers13092139
pii: cancers13092139
lyricists_name: Heavey, Susan
lyricists_id: SHEAV73
actors_name: Flynn, Bernadette
actors_id: BFFLY94
actors_role: owner
full_text_status: public
publication: Cancers
volume: 13
number: 9
article_number: 2139
event_location: Switzerland
citation:        Moore, G;    Lightner, C;    Elbai, S;    Brady, L;    Nicholson, S;    Ryan, R;    O'Sullivan, KE;                             ... Gately, K; + view all <#>        Moore, G;  Lightner, C;  Elbai, S;  Brady, L;  Nicholson, S;  Ryan, R;  O'Sullivan, KE;  O'Byrne, KJ;  Blanco-Aparicio, C;  Cuffe, S;  O'Neill, M;  Heavey, S;  Finn, SP;  Gately, K;   - view fewer <#>    (2021)    Co-Targeting PIM Kinase and PI3K/mTOR in NSCLC.                   Cancers , 13  (9)    , Article 2139.  10.3390/cancers13092139 <https://doi.org/10.3390/cancers13092139>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10127656/1/cancers-13-02139-v3.pdf